Process for the preparation of decahydro-2a,4a,6a,8a-tetraazacyclopent[fg]acenaphthylene and functionalized derivatives

ABSTRACT

A process for the preparation of compound of formula (I A), decahydro-2a,4a,6a,8a-tetraazacyclopent[fg]accnaphthylene and the corresponding functionalized compounds of general formula (1), intermediates for the preparation of 1,4,7,10-tetraazacyclododecane (II A) and corresponding derivatives (II), by preparation of compounds of general formula (III) and subsequent reduction thereof.

[0001] The present invention relates to a novel process for thepreparation of the compound of formula (I A)decahydro-2a,4a,6a,8a-tetraazacyclopent-[fg]acenaphthylene, and of thecorresponding functionalized compounds having formula (I),

[0002] used for the preparation of 1,4,7,10-tetraazacyclododecane (II A)

[0003] and of the related derivatives (II), through preparation andreduction of the compounds of general formula (III), comprising thesteps shown in Scheme 1:

[0004] The preparation of 1,4,7,10-tetraazacyclododecane (commonly namedCyclen) (II A) according to the present invention is an alternative tothe conventional procedure by Richman-Atkins (see for example J. Am.Chem, Soc., 96, 2268, 1974), which is at present industrially used forthe production of compound (II A), in the form of the sulfate salt.

[0005] 1,4,7,10-Tetraazacyclododecane is the precursor for the synthesisof macrocyclic chelating agents for metal ions.

[0006] In particular, the complexes of said chelants with paramagneticmetal ions, especially with the gadolinium ion, are characterized byhigh stability and can be used in the diagnostic field of the nuclearmagnetic resonance technique.

[0007] Two gadolinium complexes, Dotarem® and Prohance®, at presentcommercially available and having a chemical structure based on Cyclen,as well as other complexes, are being studied.

[0008] It is therefore highly desirable to provide a process for thepreparation of said intermediate which is advantageous both from thecosts and environmental standpoints, avoiding for example thepreparation of the amine tosyl derivatives commonly used in theconventional Richman-Atkins synthesis.

[0009] WO 97/49691 disclosed a process for the preparation of compound(II A) by the steps shown in Scheme 2, in which the compound of formula(I A), decahydro-2a,4a,6a,8a-tetraazacyclopent[fg]acenaphthylene, is thekey intermediate for the formation of compound (II A), and is obtainableby cyclization of the intermediate (IV),octahydro-3H,6H-2a,5,6,8a-tetraazacenaphthylene, which can in its turnbe prepared from triethylenetetramine and glyoxal.

[0010] In Scheme 2, Y is —OH (glyoxal hydrate) or [—SO₃ ⁻Na⁺](Bertagnini's salt) and X is halogen or a sulfonyloxy group

[0011] Said process has however some drawbacks. The use of a halogenatedalkylating agent such as 1,2-dibromoethane or 1,2-dichloroethane (scheme2, step a) in the condensation step, although not involving particularsupplying problems, requires specific precautions during use.1,2-Dichloroethane is in fact a cancerogenic, flammable compound whichis used in strong excess in this process. This makes the recovery of thereaction solvent free from 1,2-dichloroethane difficult. Moreover thereaction yield is not very high.

[0012] Furthermore, ethylene glycol sulfonic esters have to be prepared,as they are not commercially available, and they involve the unavoidableproduction of wastes containing sulfonic acids (methanesulfonic,paratoluenesulfonic) which are to be discharged on industrial scale.

[0013] It has now surprisingly been found, and this is the object of thepresent invention, a process for the preparation of compounds of generalformula (I), comprising the steps shown in

[0014] in which X₁, X₂, R, R₁, R₂ and A have the meanings shown below.

[0015] In particular, the process for the preparation of the compoundsof general formula (I)

[0016] in which the groups R are both hydrogen, or one is hydrogen andthe other is a straight or branched C₁-C₄ alkyl group, optionallysubstituted with one or more -OPg-protected hydroxy groups, in which Pgis a hydroxy-protecting group, comprises:

[0017] step a) reacting a compound of general formula (IV),

[0018] in which, when the groups X₁ are hydrogen, the groups X₂ form a—CH₂—CH₂— group, or vice versa, the groups X₁ are a —CH₂—CH₂— group whenthe groups X₂ are hydrogen, with a compound of general formula (VI)

[0019] in which A is a group of formula —COR₁ or —CHRR₂ wherein R hasthe meaning defined above, R₁ is halogen or C₁-C₄ alkoxy and R₂ is aleaving group such as halogen or sulfonyloxy, in at least unitary molarratio, at a temperature above 50° C.;

[0020] step b) reducing the compounds obtained from step a), havinggeneral formula (III)

[0021] in which one of Y₁ or Y₂ is —CH₂—CH₂— and the other is —CO—CO— ora group of formula —COCHR, wherein R has the meaning defined above, inthe presence of an amido-reducing agent.

[0022] The compounds of formula (I) resulting from the reductionreaction at step b) of Scheme 1, can conveniently be transformed into1,4,7,10-tetraazacyclododecane derivatives (II A) having general formula(II), according to the procedure disclosed, for example, in WO 97/49691.

[0023] In the process shown in Scheme 1, compounds (IV) are prepared asdescribed in WO 97/49691.

[0024] Step a) of Scheme 1 consists in condensing compounds (IV) withcompounds (VI), operating under inert gas atmosphere (e.g. nitrogen),using at least 1 mol of compound (VI) per mol of compound (IV), at atemperature above 50° C., preferably in a range of 60 to 75° C.

[0025] The reaction can be carried out without solvent or in thepresence of a solvent, which is preferably selected from: aromaticinert, aprotic dipolar or straight or branched C₁-C₄ alcohols andpolyethers. Preferred solvents are selected from the group of: toluene,dimethylacetamide, dimethylformamide, N-methylpyrrolidone, DMSO, C₁-C₄alcohols as defined above, glyme and diglyme. Alcohols are particularlypreferred.

[0026] The reaction time ranges from 0.5 to 36 hours, depending on thesolvent and the experimental conditions.

[0027] In a further aspect of the present invention, the processdescribed in Scheme 1 can be carried out, without significantly changingthe conditions described above, by using in step a) a catalyst which hasa surprising effect on the progress of the reaction.

[0028] Significant decreases in reaction times and advantageousincreases in yields are in fact obtained, as it will be shown in theexperimental section.

[0029] Catalysts are selected from alkali or alkaline-earth metal saltsof anions of straight or branched C₁-C₄ alcohols, or heterocyclicaromatic bases.

[0030] Said catalysts are preferably selected from the group consistingof sodium methoxide, sodium ethoxide or one of the compounds of formula:

[0031] Sodium methoxide and 2-hydroxypirydine are particularly preferredand used in amounts ranging from 0.01 to 2 mol per mol of compound (IV).

[0032] Preferred compounds of formula (VI)

[0033] are those in which:

[0034] when R₁ is a halogen or a methoxy or ethoxy group; then A is agroup of formula —COR₁ in which R₁ is a halogen or a methoxy or ethoxygroup, or a —CHRR₂ group in which R is as defined above and R₂ is aleaving group, such as a halogen or a sulfonyloxy group.

[0035] Particularly preferred are the compounds of formula (VI), inwhich: when R₁ is methoxy, ethoxy, chlorine or bromine; A is a group offormula COR₁ or a CHRR₂ group, in which R₁ is chlorine, bromine, or amethoxy or ethoxy group; R is as defined above and R₂ is a leavinggroup, such as chlorine, bromine or a sulfonyloxy group.

[0036] The compounds of formula (VI) are preferably added in amountsranging from one to four mol per mol of compound (IV).

[0037] The compounds of general formula (III) resulting from thecondensation reaction at step a) of Scheme 1 can be isolated from thesolution upon completion of the reaction, either in the salified formwith an inorganic acid (e.g. halo acid) or as the free base, and canboth be recovered with usual crystallization and/or precipitationtechniques with organic solvents. Particularly suitable are, forexample, n-hexane, toluene, methanol, ethanol and n-butanol.

[0038] Compounds (III) are preferably isolated in the salified form, asthe hydrochloride, sulfate or phosphate salts.

[0039] At step b) of Scheme 1, compounds (III) are reduced to yield thecompounds of general formula (I).

[0040] The reduction is carried out by using typical amido-reducingagents. The reaction is usually carried out in dry medium and underinert gas atmosphere. Examples of methods useful for the reduction ofamides comprise the use of sodium bis(methoxyethoxy)aluminum hydride,LiAlH₄, NaBH₄ in the presence of other reagents, other hydrides andhydride complexes, the catalytic hydrogenation on platinum oxide and insolution of HCl, borane or its adducts with THF (tetrahydrofuran) or DMS(dimethylsulfide).

[0041] Sodium bis(methoxyethoxy)aluminum hydride, commercially known asVitride® or Redal®, is preferred, as it is particularly effective.

[0042] The reduction reaction is generally carried out by addingcompounds (III) to the solution containing the reducing agent, which isadded as a 70% toluene solution, in amounts ranging from 3 to 4 mol permol of compound (III), and at a reaction temperature ranging from 35° C.to the toluene reflux temperature.

[0043] The reduction reaction is preferably carried out at the refluxtemperature of the solution for 1.3 hours, using at least 3 mol ofsodium bis(methoxyethoxy)aluminum hydride in toluene solution per mol ofcompound (III).

[0044] Compound (I) resulting from the reduction reaction can beisolated either as the free base or salified, for example ashydrochloride or phosphate.

[0045] The use of sodium bis(methoxyethoxy)aluminum hydride, comparedwith LiAlH₄ and related hydrides, provides advantages both in terms ofsafety and costs of the reduction reaction: in fact, it is notpyrophoric, does not react with oxygen and is highly soluble in a numberof solvents, such as aromatic hydrocarbons and ethers, which makes iteasy to use it and to carry out the reduction reaction in moreconcentrated solutions.

[0046] At the end of the reduction, compound (I) is recovered with theusual extraction, crystallization and/or precipitation techniques, thusremoving the aluminum inorganic salts formed during the reaction.

[0047] A particularly effective isolation procedure of compound (I),also when applied on the industrial scale, consists in using a strongcationic ion resin to temporarily bind the product on the resin, fromwhich it is subsequently eluted with an ammonia aqueous solution.

[0048] A strong cationic resin, such as Amberjet® 1200, suitablyregenerated in the acidic form, or an equivalent commercial resin, ispreferably used.

[0049] The process of the invention is particularly useful for thepreparation of compound (I A) shown in the following Scheme 3.

[0050] in which

[0051] R₁ is C₁-C₄ alkoxy and compound (VI A) is added in amounts of atleast 1 mol per mol of compound (IV).

[0052] Compound (I A) can conveniently be transformed into1,4,7,10-tetraazacyclododecane (II A) or the corresponding derivative,with the procedure described in WO 96/28432, or that in WO 98/49151, andpreferably as disclosed in WO 00/53588, by hydrolysis withdiethylenetriamine in water, at pH ranging from 5 to 9, at a temperatureranging from 90 to 120° C., in the presence of 5-10 mol ofdiethylenetriamine per mol of (I A), under inert gas atmosphere or inthe air, for 12-48 h, isolating compound (II A) as thetetrahydrochloride.

[0053] Compounds of formula (VI A), in which R₁ is methoxy or ethoxy arepreferred. Particularly preferred is diethyl oxalate, which is added inamounts of at least 1 mol per mol of compound (IV), preferably inabsolute ethanol as reaction solvent and at a temperature of 60-70° C.,for a total reaction time ranging from 6 to 24 hours.

[0054] Furthermore, the process shown in the following Scheme 4 isparticularly preferred.

[0055] in which R₁ is C₁-C₄ alkoxy and A is a —CHRR₂ group wherein R andR₂ have the meanings defined above.

[0056] Particularly preferred in step a) of Scheme 4 is the use ofcompounds (VI), in which R₁ is ethoxy or methoxy and A is a group offormula —CHRR₂ in which R is H and R₂ is Cl or Br.

[0057] Particularly preferred is the use of ethyl chloroacetate ascompound (VI), in amounts of at least 1 mol per mol of compound (IV), inabsolute ethanol, at a temperature from 50 to 70° C., in the presence ofat least 1 mol of Na₂CO₃ and at least 0.02 mol of NaI per mol ofcompound (IV) and for a reaction time from 3 to 36 hours.

[0058] A further object of the invention is the preparation of bothstereoisomers of formulae (VII) and (VIII), cis and transoctahydro-2a,4a,6a,8a-tetraazacyclopent[fg]acenaphthylene-1,2-dione, asshown in Scheme 5.

[0059] Compound (IV A), prepared as described above, is reacted using instep a) the general conditions described above and diethyl oxalate asreagent.

[0060] The novel compounds of formula (VII) and (VIII) have beenisolated and characterized by X ray analysis, as exemplified in theexperimental section.

[0061] The two isomers of formulae (IX) and (X), cis and transoctahydro-2a,4a,6a, 8a-tetraazacyclopent[fg] acenaphthylene-3,4-dione,are prepared analogously, starting from (IV B)(decahydro-diimidazo-[1,2-a:2′,1′-c]pyrazine), isomer of (IV A), withdiethyl oxalate, as shown in Scheme 6.

[0062] In this case also the compounds have been recovered andcharacterized by X ray analysis.

[0063] Compound (IX) is already known in literature, whereas compound(X) is novel.

[0064] Literature (see G. Hervè, H. Bernard, Tetrahedron Lett., 40.2517-2520. 1999) described the condensation reaction of glyoxal withtriethylenetetramine, the subsequent cyclization reaction with1,2-dibromoethane to give compound (I A) and the deprotection to1,4,7,10-tetrazacyclododecane (II A). The cited paper also reports the¹³C-NMR spectra of the mixtures of the (IV A) and (IV B) cis and transstereoisomers,

[0065] and the conversion conditions of the corresponding isomers atdifferent temperatures and experimental conditions.

[0066] The same Authors (G. Hervè, H. Bernard et al. Eur. J. Org. Chem.,33-35, 2000) reported the preparation of compound (IX) by condensationof (IV B) with diethyl oxalate in ethanol at room temperature as singleisomer, whose stereochemistry is established by X rays.

[0067] It is also reported that the condensation of compound (IV C) withdiethyl oxalate

[0068] under the same conditions does not take place and prolongedheating of the solution causes polymeric products to form.

[0069] In conclusion, the process of the invention, notwithstanding thecontrary teaching found in literature, provides in good yield compounds(VII) and (VIII) starting from (IVA), and compounds (IX) and (X)starting from (IVB). Furthermore, by the process of the invention it ispossible to isolate and characterize the novel compounds (VII), (VIII)and (X).

[0070] A further object of the invention is the process for thepreparation of compounds (VII) and (VIII) starting from (IV C) as shownin the following

[0071] Scheme 7.

[0072] by condensation with diethyl oxalate, even at temperatures below50° C.

[0073] A further object of the invention are compounds of formula (III)

[0074] wherein one of Y₁ and Y₂ is —CH₂—CH₂— and the other is —CO—CO— ora group of formula —CO—CHR—, in which R is H, straight or branched C₁-C₄alkyl, optionally substituted with one more -OPg-protected hydroxygroups in which Pg is a conventional hydroxy-protective groups,preferably benzyl.

[0075] Preferred compounds of formula (III) are the compounds of formula(XII) and (XIII)

[0076] in which R is H, straight or branched C₁-C₄ alkyl, or aphenylmethoxymethyl group (R=PhCH₂OCH₂—).

[0077] Particularly preferred are compounds (VII),cis-octahydro-2a,4a,6a,8a-tetraazacyclopent[fg]acenaphthylene-1,2-dione,(VIII) transoctahydro-2a,4a,6a,8a-tetraazacyclopent[fg]acenaphthylene-1,2-dione, (X)transoctahydro-2a,4a,6a,8a-tetraazacyclopent[fg]acenaphthylene-3,4-dione,

[0078] (XII A)decahydro-2a,4a,6a,8a-tetraazacyclopent[fg]acenaphthylene-3-one, (XIIIA) decahydro-2a,4a,6a,8a-tetraazacyclopent[fg]-acenaphthylene-1-one and(XIII B)2-(phenylmethoxymethyl)-decahydro-2a,4a,6a,8a-tetraazacyclopent[fg]acenaphthylene-1-one.

[0079] A further object of the invention are the compounds of formula(I),

[0080] in which the groups R are both H or one is hydrogen and the otheris straight or branched C₁-C₄ alkyl, optionally substituted with one ormore -OPg-protected hydroxy groups, in which Pg is a hydroxy-protectivegroup.

[0081] Particularly preferred is the compound of formula (I B)

[0082] 2-phenylmethoxymethyldecahydro-2a,4a,6a,8a-tetraazacyclopent[fg]-acenaphthylene, in which R is thephenylmethoxymethyl group (R=PhCH₂OCH₂—).

[0083] A further object of the present invention is the compound offormula (XI),trans-decahydro-2a,4a,6a,8a-tetraazacyclopent[fg]acenaphthylene.

[0084] The following examples illustrate the best experimentalconditions to carry out the process of the invention.

Experimental Section

[0085] The following procedure was used for the gas-chromatographicanalysis: Instrumentation Hewlett-Packard 5890 gas-chromatographicsystem, equipped with autosampler series 7673 and HP-3365 unit. ColumnCP Sil 19 CB, 25 m × 0.32 mm, 0.52 mm film Oven temp. program: firstisotherm at 120° C. for 5 min; ramp 15° C./ min to 260° C.; secondisotherm at 260° C. for 12 min Injector Split flow rate 11.5 mL/minTemperature 250° C. Detector FID Temperature 275° C. Hydrogen pressure1.2 bars Air pressure 2.8 bars Column flow rate  1.2 μl/min Carrier gasHe₂ Column pressure 20 psi Auxiliary gas flow rate 10 mL/min Septumpurge flow rate 5 mL/min Injection  1 μl Sample concentration 20 mg/mLInternal standard Acenaphthene Internal standard  10 mg/mL concentr.:

EXAMPLE 1

[0086] Preparation of cis/trans ofoctahydro-2a,4a,6a,8a-tetraazacyclopent[fg] acenaphthylene-1,2-dione(III)

[0087] A) Preparation of3H,6H-2a,5,6,8a-octahydrotetraaza-acenaphthylene (IV A)

[0088] A suitable reactor is loaded, under mild nitrogen stream, with370.5 g of straight hydrated triethylenetetramine (TETA), 2 kg of waterand 296.4 g of calcium hydroxide. Then a 9% (w/w) glyoxal aqueoussolution prepared by mixing 290 g of 40% solution with 1 kg of water,stirred in nitrogen blanket and cooled to 0-5° C., is added to theresulting suspension. After completion of the addition, the mixture iskept at 5° C. for 1 h, and filtered through Celite® previously washedwith 0.5 kg of water. The filtrate is evaporated to dryness underreduced pressure.

[0089] The product is not subjected to purification but is directly usedfor the subsequent reaction.

[0090] Yield: 98.5% (on dry matter)

[0091] GC assay: >75% (% area)

[0092] B) Preparation of Compound (III) and Isolation as Hydrochloride

[0093] Into a 1 L reactor, kept in nitrogen atmosphere and containing asolution of 50 g (0.297 mol) of compound (IV) prepared as described inexample 1A) in 0.4 L of ethanol, 130 g (0.891 mol) of diethyl oxalateare added. The resulting solution is kept under magnetic stirring at 68°C. for 24 hours, then partially concentrated under reduced pressure to384 g. 86.4 g (0.296 mol) of a 12.5% w/w HCl ethanol solution aredropped into the reaction mixture and kept under magnetic stirring for40 minutes. The suspension is kept for 45 minutes under magneticstirring and the resulting solid is filtered and washed on the filterwith 75 mL of ethanol. The humid solid is dried in a static dryer undervacuum at 40° C. for 12 hours, to obtain 38.4 g (0.146 mol) of thedesired compound with the following analytical characteristics:

[0094] GC assay: 94.6% (% area)

[0095] Recovery yield: 49%

[0096] The ¹H-NMR, ¹³C-NMR, IR and MS spectra are consistent with theindicated structure.

EXAMPLE 2

[0097] Preparation of Compound (III), Free Base

[0098] In a suitable reactor, in nitrogen atmosphere, a solution of 50.5g (0.3 mol) of compound (IV) prepared as described in example 1A) in 0.4L of ethanol and 131.5 g (0.9 mol) of diethyl oxalate are loaded. Thesolution is heated to 68° C. and kept under magnetic stirring at thistemperature for 27 hours. The solvent is evaporated off under reducedpressure to a residue weighing 150 g, and a solution of 123 mL oftoluene and 13 mL of ethanol is added. The resulting suspension is kentunder magnetic stirring for 2 hours, then filtered through porousseptum. The solid is washed with 40 mL of an ethanol/toluene=1/lsolution (v/v), then dried in a static dryer under vacuum at 40° C. for12 hours, to obtain 31 g (0.132 mol) of the desired compound having thefollowing analytical characteristics:

[0099] GC assay: 95% (% area)

[0100] Yield: 44%

[0101] The ¹H-NMR, ¹³C-NMR, IR and MS spectra are consistent with theindicated structure.

EXAMPLE 3

[0102] Preparation of Compound (III) by Reaction in Mass

[0103] Into a 50 mL round-bottom flask equipped with reflux condenser,thermometer and mechanical stirrer, kept in nitrogen atmosphere, 12 g(0.071 mol) of product prepared as in example 1 A) and 11.9 g (0.078mol) of diethyl oxalate are loaded. The mixture is heated in mass at 65°C. for 5 hours, then added with 1.19 g (0.0078 mol) of diethyl oxalateand heating is continued for 6 hours. The mixture is left to cool toroom temperature and the ethanol formed during the reaction is distilledoff under partial vacuum. The product is purified by chromatography on asilica gel column (eluent: CHCl₃/methanol=8/2 V/V), to obtain 11.2 g(0.050 mol) of the desired compound having the following analyticalcharacteristics:

[0104] GC assay: 98 (% area)

[0105] Yield: 60%

EXAMPLE 4

[0106] Preparation of Compound (III) in the Presence of2-hydroxypirydine

[0107] Into a solution of 50.5 g (0.3 mol) of compound (IV) prepared asdescribed in example 1A) in 0.4 L of ethanol, under magnetic stirringand nitrogen atmosphere, 14.1 g (0.148 mol) of 2-hydroxypyridine and86.80 g (0.594 mol) of dethyl oxalate are added. The solution is kept at68° C. for 6 hours, then partially concentrated, under vacuum partial,to a weight of 122 g.

[0108] The residual product is added with 170 mL of toluene and 18 mL ofethanol and the suspension is kept under magnetic stirring for 17 hours,then filtered and washed on filter with an ethanol/toluene 1/1 solution(v/v). The product is dried in a static dryer to obtain 41 g (0.179 mol)of the desired compound having the following analytical characteristics:

[0109] GC assay: 96.9%

[0110] Yield: 60%

[0111] The ¹H-NMR, ¹³C-NMR, IR and MS spectra are consistent with theindicated structure.

EXAMPLE 5

[0112] Preparation of Compound (III) in the Presence of Sodium Methoxide

[0113] In a solution of 53.5 g (0.318 mol) of compound (IV) in 0.4 L ofethanol, under magnetic stirring and nitrogen atmosphere, 17.2 g (0.318mol) of sodium methoxide are added. The suspension is stirred untilcomplete dissolution, and then is added 92.9 c, (0.636 mol) of diethyloxalate. The mixture is heated to 68° C. and kept at this temperaturefor 1.5 hours. The solution is partially concentrated and then 130 mLethanol is added to the residue at 70° C.

[0114] The resulting suspension is kept for 72 hours under mechanicalstirring at 23° C. The solid product is filtered, washed with 45 mL ofethanol and dried in a static dryer under partial vacuum to obtain 35.3g of the desired compound (0.159 mol) having the following analyticalcharacteristics:

[0115] G.C. assay: 95%

[0116] Yield: 50%

[0117] The ¹H-NMR, ¹³C-NMR, IR and MS spectra are consistent with theindicated structure.

EXAMPLE 6

[0118] Preparation of (VII) cisoctahydro-2a,4a,6a,8a-tetraazacyclo-pent[fg]-acenaphthylene-1,2-dione

[0119] The intermediate of formula (IV A), obtained as described inpreparation 1A), is purified through salification as acetate, accordingto the following procedure:

[0120] 15 g (0.09 mol) of compound prepared as described in preparation1A) are dissolved in 100 g of toluene, then 5.5 g of conc. acetic acidsolution are dropped into the solution and the resulting suspension isstirred for 10 minutes. The resulting solid is filtered, washed withtoluene, and dried under vacuum at 30° C. to obtain 14.1 g of compound(IV C) as monoacetate.

[0121] GC assay: 98% (% area)

[0122] Recovery yield: 70%

[0123] 2 g of the above prepared compound are dissolved in a 10% NaOHsolution and extracted with chloroform. The separated organic phase isdried, filtered and evaporated to a residue weighing 1 g (0.006 mol),which is dissolved in 10 mL of ethanol and added with 2.6 g (0.018 mol)of diethyl oxalate. The resulting solution is heated at 70° C. for 12hours and concentrated under vacuum to a solid residue. The crudeproduct is purified by silica gel chromatography, using a CHCl₃/MeOH=8/2eluent mixture (v/v), to obtain 0.6 g of compound (VII) having thefollowing analytical characteristics:

[0124] GC assay: 99 (% area)

[0125] The ¹H-NMR, ¹³C-NMR, IR and MS spectra are consistent with theindicated structure.

EXAMPLE 7

[0126] Preparation of Compounds (VII) and (VIII), cis and transoctahydro-2a,4a,6a,8a-tetraazacyclopent[fg]acenaphthylene-1,2-dione

[0127] A) Preparation of (VII) cisoctahydro-2a,4a,6a,8a-tetraazacyclopent[fg]-acenaphthylene-1,2-dione.

[0128] In a 1 L reactor, in nitrogen atmosphere, 160 mL of absoluteethanol, 21 g (0.125 mol) of product prepared as in example 1 A), 6.74 g(0.125 mol) of sodium methoxide and 36.5 g (0.250 mol) of diethyloxalate are loaded. The solution is heated and kept at 68° C. for 2hours, then cooled to room temperature and 12.3 g of a 37% HCl solution(0.125 mol) are dropped therein. The resulting suspension is filteredthrough Celite and the filtrate is evaporated to dryness to give crudecompound (VIII), which will be used for the subsequent isolation of(VIII) (see part B).

[0129] The product on the filter is suspended in deionized water andfiltered through Celite. In the filtrate 6.9 g (0.065 mol) of Na₂CO₃ areadded and the resulting suspension is evaporated to a residue. The solidresidue is suspended in methanol and filtered at 60° C. The resultingsolution is left to spontaneously cool to 23° C. and the solid productobtained from the crystallization is filtered and dried under vacuum at40° C. for 12 hours, to obtain 7.5 g of dry product having the followinganalytical characteristics:

[0130] GC assay: 100 (% area)

[0131] The ¹H-NMR, ¹³C-NMR, IR, MS and the solid state structureobtained by X ray diffractometry are consistent with the indicatedstructure.

[0132] B) Isolation of (VIII) transoctahydro-2a,4a,6a,8a-tetraazacyclopent[fg]-acenaphthylene-1,2-dione

[0133] Crude compound (VIII) (see A) is purified by silica gelchromatography using a CHCl₃/MeOH/NH₃ eluent mixture. The fractionscontaining the purified product are combined and evaporated to a solidresidue. The resulting product is recrystallized from methanol to obtaina product, which is dried under vacuum at 40° C. for 12 hours to yield1.5 g of compound having following analytical characteristics:

[0134] GC assay: 100 (% area)

[0135] The ¹H-NMR, ¹³C-NMR, IR, MS and the solid state structureobtained by X ray diffractometry are consistent with the indicatedstructure.

EXAMPLE 8

[0136] Preparation and Isolation of (X) transoctahydro-2a,4a,6a,8a-tetraazacyclopent[fg]acenaphthylene-3,4-dione

[0137] A) Preparation of decahydro-diimidazo-[1,2-a:2′,1′-c]pyrazine (IVB)

[0138] In a suitable 2 L reactor, maintained under nitrogen atmosphere,50 g (305 mmol) of straight hydrated TETA and 1 L of absolute ethanolare loaded. To the solution 44.5 g (305 mmol) of a 40% glyoxal solutionare added. After completion of the addition, the solution is kept undermagnetic stirring at 23° C. for 17 hours. The resulting solution isconcentrated under partial vacuum to an oily residue.

[0139] GC assay: 75% (% area)

[0140] B) Preparation and Isolation of Compound (X)

[0141] In a 0.25 L round-bottom flask equipped with mechanical stirrerand thermometer, under nitrogen atmosphere, 5.5 g (0.0326 mol) ofcompound (IV B) prepared as described above in Example 8 A), 80 mL ofabsolute ethanol, 0.88 g (0.0163 mol) of sodium methoxide and 2,38 g(0.0163 mol) of diethyl oxalate are loaded. The resulting solution isheated at 68° C. for 8 hours and, after partial concentration undervacuum, is left to spontaneously cool to 23° C. The crystallized solidproduct is filtered and recrystallized from methanol. The product isrecrystallized, filtered and dried under vacuum in a static dryer at 40°C. for 12 hours, to yield 0.5 g of the desired compound having thefollowing analytical characteristics:

[0142] GC assay: 100 (% area)

[0143] The ¹H-NMR, ¹³C-NMR, IR, MS and the solid state structureobtained by X ray diffractometry are consistent with the indicatedstructure.

EXAMPLE 9

[0144] Preparation and Isolation of (IX) cisoctahydro-2a,4a,6a,8a-tetraazacyclopent[fg] acenaphthylene-3,4-dione

[0145] In a 1 L reactor equipped with mechanical stirrer, thermometer,reflux condenser and nitrogen blanket, 30 g (0.178 mol) of productprepared as in example 8 A), 225 mL of absolute ethanol and 13 g (0.089mol) of diethyl oxalate are loaded. The solution is heated and kept at68° C. for 18 hours, and then 2.6 g (0.0178 mol) of diethyl oxalate areadded and the solution is kept at 68° C. for 4 hours. The solution isleft to cool to 23° C. and the crystallized solid is filtered andrecrystallized from methanol. The resulting product is dried at 40° C.for 12 hours to a weight of 6.2 g (0.0279 mol) and has the followinganalytical characteristics:

[0146] GC assay: 100 (% area)

[0147] The ¹H-NMR, ¹³C-NMR, IR, MS and the solid state structureobtained by X ray diffractometry are consistent with the indicatedstructure.

EXAMPLE 10

[0148] Preparation of decahydro-2a,4a,6a,8a-tetraazacyclopent[fg]acenaphthylene-1-one (XIII A)

[0149] In a 1 L round-bottom flask containing 0.2 L of ethanol and 18 g(0.107 mol) of compound (IV A) prepared as in example 1 A, are loaded22.7 g (0.214 mol) of Na₂CO₃, 1.6 g (0.0107 mol) of NaI and 26.2 g(0.214 mol) of ethyl chloroacetate. The resulting suspension is stirredfor 24 hours at 23° C., then filtered through porous septum and theresulting filtrate is evaporated to dryness.

[0150] In a 0.25 L round-bottom flask equipped with mechanical stirrer,reflux condenser and nitrogen blanket and thermometer, are placed 16 gof the above prepared product, 60 mL of ethanol, and 1.47 g of2-pyrydinol (0.016 mol). The resulting solution is refluxed for 48hours. The solution is cooled and evaporated to dryness. The residue ispurified by silica gel chromatography with a CHCl₃/MeOH=95/5 (v/v)eluent solution. The fractions containing the purified product arecombined and concentrated under partial vacuum to a solid residue, toobtain 10 g of purified compound having the following analyticalcharacteristics:

[0151] Yield 45%

[0152] GC assay: 80 (% area)

EXAMPLE 11

[0153] Preparation of2-(phenylmethoxymethyl)-decahydro-2a,4a,6a,8a-tetraazacyclopent[fg]acenaphthylene-1-one(XIII B)

[0154] In a 250 mL round-bottom flask 100 mL of ethanol and 10 g (0.059mol) of compound (IV A) prepared as in example 1A are loaded, then 6.25(0.059 mol) of sodium carbonate, 0.45 g (0.03 mol) of NaI and 21.4 g(0.088 mol) of ethyl 3-benzyloxy-2-chloro-propionate are added. Thesuspension is stirred for 36 hours at room temperature, then filtered.The solid is washed with 30 mL of ethanol. The filtrate is partiallyconcentrated to 120 g and added with 2.66 (0.029 mol) of 2-pyrydinol.The resulting solution is refluxed for 48 hours, then evaporated and theresidue is purified by silica gel chromatography, eluting withchloroform/methanol=9/1. The fractions containing the purified productare combined and evaporated to a residue, to obtain 7.4 g of compound.

[0155] The ¹H-NMR, ¹³C-NMR, IR and MS spectra are consistent with theindicated structure.

EXAMPLE 12

[0156] Preparation of decahydro-2a,4a,6a,8a-tetraazacyclopent[fg]acenaphthylene (I A)

[0157] In a 1 L round-bottom flask containing 100.8 g (70% in toluene;0.349 mol) of Vitride® in 0.2 L of toluene, kept in nitrogen atmosphereand magnetic stirring, are added 19.4 g (0.087 mol) of compound (III),prepared as in example 5. The resulting suspension is heated and kept at112° C. for 1 hour.

[0158] The solution is left to cool to 22° C., then 58 mL of a 5% w/wNaOH aqueous solution are slowly dropped therein. The two resultingphases are separated and the aqueous phase is extracted with toluene.The first separated organic phase and those deriving from the tolueneextraction are combined, evaporated to dryness, and the residue isdissolved in 80 mL of deionized water. The aqueous solution ispercolated onto a column containing 165 mL of Amberjet 1200® cationicresin, previously regenerated in the H⁺ form. Water is at firstpercolated on the resin bed to neutral eluate, and then a 2.5% NH₄OHsolution is percolated. The ammonia fractions containing the product areevaporated to dryness. The solid residue is extracted at 50° C. withn-hexane and the resulting solutions are combined and further evaporatedunder partial vacuum to a residue. The resulting solid product is driedin the presence of P₂O₅ to obtain 14.2 g (0.073 mol) of compound havingthe following analytical characteristics:

[0159] Tit. G.C.: 100%

[0160] Yield: 84%

[0161] The ¹H-NMR, ¹³C-NMR, IR and MS spectra are consistent with theindicated structure.

EXAMPLE 13

[0162] Preparation ofdecahydro-2a,4a,6a,8a-tetraazacyclopent[fg]ace-naphthylene (IA) startingfrom decahydro-2a,4a,6a,8a-tetraazacyclo-pent[fg]acenaphthylene-1-one(XIII A)

[0163] In a 0.1 L round-bottom flask containing 10 mL of toluene and 2.8g (70% toluene; 0.0096 mol) of Redal®, maintained under mechanicalstirring and nitrogen blanket, 1 g (0.004 mol) of the compound ofexample 10 is added at 45° C. The solution is heated to 100° C. for 1hour, then cooled to room temperature and added with 1.5 mL of 5% NaOH.The two resulting phases are separated and the aqueous phase isextracted with toluene. The combined organic phases are concentratedunder vacuum to a solid residue. The resulting product is purified bysilica gel chromatography eluting with a CHCl₃/MeOH=8/2 mixture (v/v).The fractions containing the purified product are combined andconcentrated to a solid residue weighing 0.60 g.

[0164] Yield: 77%

[0165] GC assay: 100 (% area)

[0166] The ¹H-NMR, ¹³C-NMR, IR and MS spectra are consistent with theindicated structure.

EXAMPLE 14

[0167] Preparation of2-phenylmethoxymethyl-decahydro-2a,4a,6a,8a-tetraazacyclo-pent[fg]acenaphthylene

[0168] Compound (I B) is obtained by using compound (XIII B) as startingproduct and the reductive conditions as described in example 13.

[0169] The ¹H-NMR, ¹³C-NMR, IR and MS spectra are consistent with theindicated structure.

EXAMPLE 15

[0170] Preparation oftrans-decahydro-2a,4a,6a,8a-tetraazacyclopent[fg]acenaphthylene (XI)

[0171] Compound (XI) is isolated from the isomeric cis/trans mixtureobtained from example 12, by silica gel chromatography, eluting withCHCl₃/CH₃OH=9:1. The resulting compound has the following analyticalcharacteristics:

[0172] GC assay: 100 (% area)

[0173] The ¹H-NMR, ¹³C-NMR, IR and MS spectra are consistent with theindicated structure.

1. A process for the preparation of the compounds of general formula (I)

in which the groups R are both hydrogen, or one is hydrogen and theother is a straight or branched C₁-C₄ alkyl group, optionallysubstituted with one or more -OPg-protected hydroxy groups, in which Pgis a hydroxy-protecting group, which process comprises: step a) reactinga compound of general formula (IV),

in which, when the groups X₁ are hydrogen, the groups X₂ form a—CH₂—CH₂— group, or vice versa, the groups X₁ are a —CH₂—CH₂— group whenthe groups X₂ are hydrogen, with a compound of general formula (VI)

in which A is a group of formula —COR₁ or —CHRR₂ wherein R has themeaning defined above, R₁ is halogen or a C₁-C₄ alkoxy group and R₂ is aleaving group such as halogen or sulfonyloxy, in at least unitary molarratio, at a temperature above 50° C.; step b) reducing the compoundsobtained from step a), having general formula (III)

in which one of Y₁ or Y₂ is —CH₂—CH₂— and the other is —CO—CO— or agroup of formula —COCHR, wherein R has the meaning defined above, in thepresence of an amido-reducing agent.
 2. A process as claimed in claim 1wherein in the compounds of formula (III), R is H or straight orbranched C₁-C₄ alkyl, optionally substituted with one or more -OPggroups in which Pg is benzyl.
 3. A process as claimed in claim 1 whereinthe reaction of compound of formula (IV) with compound of formula (VI)is carried out under inert gas atmosphere, using at least 1 mol ofcompound (VI) per mol of compound (IV), in the presence of a solventselected from: aromatic inert, aprotic dipolar, or straight or branchedC₁-C₄ alcohols and polyethers.
 4. A process as claimed in claim 3,wherein the solvent is selected from the group consisting of: toluene,dimethylacetamide, dimethylformamide, N-methylpyrrolidone, DMSO, C₁-C₄alcohols, glyme and diglyme.
 5. A process as claimed in claims 1-2,wherein no solvent is used in step a).
 6. A process as claimed in claims1-5, in which step a) is carried out in the presence of alkali oralkaline-earth metal salts of anions of straight or branched C₁-C₄alcohols, or of heterocyclic aromatic bases, as catalysts.
 7. A processas claimed in claims 1-6, in which step a) is carried out in thepresence of a catalyst selected from the group consisting of sodiummethoxide, sodium ethoxide, or one of the compounds of formulae:


8. A process as claimed in claims 1-7, wherein the catalyst is sodiummethoxide or 2-hydroxypyridine, in amounts ranging from 0.01 to 2 molper mol of compound (IV).
 9. A process as claimed in claims 1-8, whereincompound of formula (III) is recovered upon completion of the reaction,either as a salt with an inorganic acid selected from the groupconsisting of hydrochloric, sulfuric and phosphoric acids, or as thefree base.
 10. A process as claimed in claims 1-9, wherein the reductionof compound (III) is carried out in dry medium and under inertatmosphere, using a reducing agent selected from the group consistingof: sodium bis(methoxyethoxy)aluminum hydride, LiAlH₄, NaBH₄, borane orthe tetrahydrofuran or dimethyl sulfide adducts thereof or by catalytichydrogenation on platinum oxide and in HCl solution.
 11. A process asclaimed in claim 10, wherein are used sodium bis(methoxyethoxy)aluminumhydride or catalytic hydrogenation on platinum oxide in HCl aqueoussolution.
 12. A process as claimed in claim 11, wherein the reducingagent is sodium bis(methoxyethoxy)aluminum hydride, in amounts rangingfrom 3 to 4 mol per mol of compound (III), at a reaction temperatureabove 35° C.
 13. A process as claimed in claims 9-12, wherein compoundof formula (I) is isolated as free base or salified as hydrochloride orphosphate.
 14. A process as claimed in claim 13, wherein the compound offormula (I) is isolated at the end of the process by using a cationicion exchange resin.
 15. A process as claimed in claims 1-14 wherein isused a compound of formula (VI A)

wherein R₁ is a C₁-C₄ alkoxy group.
 16. A process as claimed in claim15, wherein in compound of formula (VI A), R₁ is methoxy or ethoxy. 17.A process as claimed in claim 16, wherein compound (VI A) is used inamounts of at least 1 mol per mol of compound (IV), in absolute ethanolas reaction solvent and at a temperature of 60-70° C.
 18. A process asclaimed in claims 1-14, wherein is used a compound (VI), in which R₁ isa C₁-C₄ alkoxy group and A is a —CHRR₂ group wherein R and R₂ have themeanings defined above.
 19. A process as claimed in claim 18, wherein isused a compound of formula (VI), in which R₁ is methoxy or ethoxy, and Ais a group of formula —CHRR₂ in which R is H and R₂ is Cl or Br.
 20. Aprocess as claimed in claim 19, wherein in step b) ethyl chloroacetateis used as compound of formula (VI), in amounts of at least 1 mol permol of compound (IV), in absolute ethanol, at a temperature ranging from20 to 70° C., in the presence of at least 2 mol of Na₂CO₃ per mol ofcompound (IV) and for a reaction time ranging from 3 to 24 hours. 21.Compounds of general formula (III),

wherein one of Y₁ or Y₂ is —CH₂—CH₂— and the other is —CO—CO— or a groupof formula COCHR wherein R is H or straight or branched C₁-C₄ alkyl,optionally substituted with one more -OPg groups in which Pg is asdefined above.
 22. Compounds as claimed in claim 21 wherein R is H,straight or branched C₁-C₄ alkyl, optionally substituted with one ormore benzyl-protected hydroxy groups.
 23. Compounds as claimed in claims21-22, of formulae (XII) and (XIII)

wherein R has the meaning defined in claims 21-22.
 24. Compounds asclaimed in claim 23, of formulae (XII A), (XIII A) and (XIII B)


25. Compounds as claimed in claim 21, of formula (VII), (VIII) and (X)


26. Compounds of general formula (I)

wherein the groups R, defined as in claims 21-22, are both hydrogen orone is hydrogen and the other is straight or branched C₁-C₄ alkyl,optionally substituted with one or more groups -OPg in which Pg is ahydroxy-protecting group.
 27. A compound of formula (I B)

which is2-phenylmethoxymethyl-decahydro-2a,4a,6a,8a-tetraazacyclo-pent[fg]acenaphthyl ene.
 28. A compound of formula (XI)

which istrans-decahydro-2a,4a,6a,8a-tetraazacyclopent[fg]acenaphthylene.